CN115297781A

CN115297781A - Radar system for dynamic monitoring and guidance of clinical trials in operation

Info

Publication number: CN115297781A
Application number: CN202180007898.3A
Authority: CN
Inventors: 谢泰亮
Original assignee: Bright Clinical Research Ltd
Current assignee: Bright Clinical Research Ltd
Priority date: 2020-02-26
Filing date: 2021-02-26
Publication date: 2022-11-04
Also published as: WO2021171255A1; JP2023507668A; TW202201421A; EP4110187A1; JP2024070857A; KR20220119499A; AU2023278032A1; AU2021226201B2; JP7403884B2; KR20230107914A; EP4110187A4; KR102555679B1; AU2021226201A1; US20230077323A1

Abstract

The present invention constitutes a "radar" system for dynamically monitoring and guiding clinical trials in operation. In one embodiment, the system divides the data space into three main regions, including "good", "optimistic", and "bad", to reflect the trial status. In one embodiment, the bad areas comprise invalid areas and the good areas comprise successful areas. In one embodiment, the boundaries defining these regions may be adjusted as the clinical trial runs. In one embodiment, cumulative treatment effects, data trends, stopping boundaries, trajectories, and other information may be displayed graphically on a "radar" screen. In one embodiment, the system learns from observed and accumulated data and performs simulations to intelligently guide the experiment. In one embodiment, the system is used to re-analyze or diagnose a completed clinical trial and provide guidance for clinical trial design or modification.

Description

Radar system for dynamic monitoring and guidance of clinical trials in operation

RELATED APPLICATIONS

The present application claims priority from U.S. provisional application No. 62/981,954, filed on 26/2020, U.S. provisional application No. 63/016,572, filed on 28/4/2020, U.S. provisional application No. 63/058,839, filed on 30/7/2020, and U.S. provisional application No. 63/138,422, filed on 16/1/2021. All of the foregoing applications are incorporated by reference herein in their entirety. This application also incorporates a number of publications. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

Technical Field

The present invention relates to a system and related method for dynamically and adjustably monitoring an on-the-fly clinical trial, referred to as Dynamic Data Monitoring (DDM). Specifically, the present invention divides the data space into three main regions: "good area", "optimistic area" and "bad area" to construct a clinical trial "radar screen". The "defective area" is further divided into "defective" and "invalid" areas. On the screen, cumulative treatment effects, data trends, stopping boundaries, trajectories and other information are displayed dynamically and graphically. As a metaphor, a clinical trial is in operation as if an aircraft is flying in the air, the cumulative treatment effect is as if the flight path, the different areas represent air or weather conditions in the air, the Independent Data Monitoring Committee (IDMC) plays a role as a ground controller, and the "destination" is where the treatment effect crosses the success limit at the completion of the study (i.e., significant differences are achieved).

Background

69.3% of phase II clinical trials have been reported to fail to reach phase III [ 1%]. The high failure rate may have many causes, including the ineffectiveness of the experimental treatment itself or safety issues. Another reason may be related to deficiencies or limitations of traditional research designs. In designing a clinical trial, one will typically base its prior knowledge of experimental treatment on earlier studies to assume the expected therapeutic effect. The assumed therapeutic effect is used to determine the initial sample number (N) ₀ ) I.e. the initial maximum amount of information. As the trial progresses, the information score is defined as the number of enrolled patients (N) in N ₀ At t = N/N ₀ And (4) showing. The challenge is that such estimates from previous or external sources may not be reliable as the number of patients or medical procedures may differ. Thus, a substantially previously fixed maximum amount of information, or a specific number of samples, may not provide the required assay force. An overly optimistic postulated treatment would result in inadequate diagnostic power (or too low a number of samples), while a pessimistic treatment would result in an unnecessarily large number of studies. A fixed sample number (SS) may result in an experiment that is optimistic but lacks significant differences, or an experiment that was "hopeless" at an early stage but unknowingly proceeded to a final stage. Most clinical trials are randomized and double blind. Thus, patients, trial researchers (physicians), and trial delegates or other interested parties may not be aware of their risks or benefits because they do not have access to the data of the clinical trial being run.

Conventional fixed sample count design remains a common practice in clinical trials, particularly for early stage studies, where experimental design has evolved over the past decades to improve trial efficiency. One of the most widely used methods is cluster-successive design (GSD), especially long-term research. In classical GSD, phase analysis is performed at predefined time points and has a predetermined efficacy or ineffectiveness threshold (Pocock, 1977, [2]; O' Brien and Fleming (OBF), 1979, [3]; tsiatis,1982, [4 ]). The alpha consumption function method provides a flexible analysis schedule and frequency during the test, greatly enhancing classical GSD (Lan and DeMets,1983, [5]; lan and Wittes,1988, [6]; lan and DeMets,1989, [7]; lan, rosenberger and Lachin,1993[8 ]). The sample number recalculation (SSR) program based on conditional determinism (CP) was developed in the early 90 s using interim data of the current test itself, aiming at ensuring research determinism by increasing the maximum amount of information originally specified in the program (Wittes and Brittain,1990[9]; shih,1992[10]; gould and Shih,1992[11]; herson and Wittes,1993[12 ]). See Shih (2001) reviews of GSDs and SSRs [13]. GSDs with SSRs form the so-called Adaptive GSD (AGSD) (Bauer and Kohne (1994) [14], proschan and Hunsberger (1995) [15], cui, hung and Wang (1999) [16], li et al (2002) [17], chen, deMet and Lan (2004) [18], posch et al (2005) [19], gao, ware and Mehta (2008) [20], gao, liu and Mehta (2013) [21], bowden and der Man (2014) [22], and Shih, li and Wang (2016) [23 ]). Both GSD and AGSD are commonly used to improve assay efficiency. However, the following limitations and challenges still exist.

First, the time of interim analysis and/or SSR is predefined. Conventionally, practitioners often recommend performing the test at run-half. Due to fluctuations in the accumulated data, the trial was run to half the time point at which it was likely to be wrong, and in the two extreme cases, as shown in the table below, the interim analysis may not reflect the true state (trend) of the data.

TABLE 1. Extremes with analysis during preplanning period

δ is the therapeutic effect, the assay force is 90%, and σ =1 is assumed.

Second, many phase II-III clinical trials have established the Independent Data Monitoring Committee (IDMC) to periodically review safety and/or efficacy data for the trial in operation. IDMC is usually prescribed every 3 or 6 months, depending on the kind of disease and the particular intervention. IDMC may be more frequently prescribed for oncology trials with new therapies, relative to non-life threatening diseases. Committees may have more frequent meetings at the early stages of the trial and have an early understanding of the safety of the trial. Current practice of IDMC involves three parties: consignee, independent Statistical Group (ISG) and IDMC. It is the responsibility of the test principal to guide and manage the research being conducted. The ISG prepares blinded data and blinded packets according to the planned data truncation date (typically one or more months before the IDMC meeting): tables, lists and diagrams (TLF). The preparation usually takes about 2-3 months. IDMC members receive packets one week prior to the IDMC conference and will review during the conference.

There are practical problems with current IDMC practice. First, the presented packet is simply a "snapshot" of the data. In other words, as data accumulates, trends in treatment efficacy (efficacy or safety) are not presented to IDMC. IDMC snapshot-based suggestions may differ from suggestions based on "continuous" data tracks, as shown in the following figure.

As shown in fig. 1A, IDMC may suggest that both trials proceed in

periods

1 and 2, while in fig. 1B, a negative trend may result in IDMC suggesting termination of trial B. Second, the current IDMC procedure has logistical problems. The ISG takes approximately 2-3 months to prepare a packet for IDMC. For blind experiments, blinding is usually handled by ISG. Although it is assumed that data integrity can be preserved at the ISG level, there is no guarantee that 100% is free of any human error during this manual process.

Third, the statistical theory of GSD/AGSD assumes a Brownian motion model on the observed data, bringing about a straight-line trend to the observed data (Proschan, lan and Wittes,2006[24 ]). In fact, this assumption may be violated for some known or unknown reasons, such as accumulation of operating experience, changes in the plan or patient, etc. Once this assumption is violated, the statistical tests, models, predictions, and conclusions may no longer be valid.

FIG. 2 shows Lan and Wittes (1988) [ 6)]As defined in (1), and Scharfstein et al (1997) [40 ]]The data history displayed by the B-value, B (t), related to the mentioned Rules and Asymptotic (RAL) assay statistics, versus the information time, t, was studied until interim analysis of t = 0.75.

Wherein Z (t) is a Z assay based on RAL statistics. Under the brownian motion model, we expect to see a linear trend of B (t). However, it may be doubtful here that three piecewise linear trends are more suitable than one linear trend. This visual inspection is not a formal diagnostic test. However, the entire data history up to the run-time analysis clearly helps to suggest some sensitivity analysis at t = 0.75.

Specifically, we begin with the following known Conditional Power (CP) results, such as Proschan, lan, and Wittes (2006) [24]]The results given in (1). Let C be _α The final threshold for B (1) is reached when α =0.025, which equals 1.96, when no multiplicity adjustment is involved. Under B (t) conditions, the CP at the information time t is given by

Where θ is the drift parameter and the true (unknown) therapeutic effect is represented by the value of B. There are various methods for selecting θ in (1). The selection being dependent on the monitored target, e.g. contradictory assumption H _A The number of raw samples and the assay force are based on the value of (1); at H ₀ The lower is 0; empirical point estimation

Based on

Some confidence limits of; or some combination of the above, and may even include other external information that needs to be detected or a view of clinically significant action, etc. Further, at the previous θ pointThe average value of CP (theta, t) is obtained on the cloth, and the predicted assay force can be obtained. The DDM provides all of these options. The most popular choice in the literature is

It belongs to a "snapshot" of the data at time t.

When the graph shown in fig. 2 indicates that piecewise linear trends fit the data path better than a single slope, we may wish to perform some sensitivity analysis on the CP by considering other choices of θ. For example, FIG. 2 shows a time period (0, t) ₁ )、(t ₁ ，t ₂ ) And (t) ₂ ，t ₃ ) The slope of the line segments is respectively

A weighted average w may be used ₁ S ₁ +w ₂ S ₂ +w ₃ S ₃ . It is generally reasonable to depreciate earlier trends based on the maturity of the data and/or the nature of the therapeutic effect. It is noted that,

also a weighted average, whose weight is proportional to the length of the line segment

Rather than to chronological order. The weights change when multiple interim analyses are performed, and this approach will become a moving (weighted) average of the CP calculated from time to time, using the entire up-to-date data path, rather than a "snapshot" of each point in time. In DDM, we propose to use this approach when the data appears to exhibit non-linear drift.

As previously mentioned, most clinical trials are randomized and double-blind. Thus, patients, trial researchers (physicians), and trial delegators or other interested parties may not be aware of their risks or benefits because they do not have the data rights of the clinical trial. In one embodiment, the radar system of the present invention is characterized by automatically blinding data without human intervention and continuously evaluating risk based on the blinded data.

Today, most clinical trials are managed through Electronic Data Collection (EDC) systems. Treatment and drug dispensing is managed by an Interactive Response Technology (IRT) system. By combining EDC and IRT together, the therapeutic effect on the target endpoint (safety or efficacy) can be automatically and continuously calculated. This automation has enabled us to develop a computer system for dynamically monitoring the test being run and intelligently predicting the trajectory of the test results.

The invention constructs a clinical test radar system for dynamically monitoring and guiding a test in operation, wherein:

(1) Cumulative treatment effects and associated statistics (CP, sample number ratio, etc.) can be automatically calculated.

(2) Model linearity can be automatically evaluated.

(3) Data trends and trajectories can be dynamically estimated

(4) The reliability of the estimated trend and trajectory can be evaluated by simulations.

(5) The decision can be made intelligently.

In one embodiment, the present invention provides a calculator-based "radar" system for clinical trials, in which the data space is divided into four regions: good, optimistic, bad and invalid as shown in fig. 3A and 3B. The trial was in the expected good state when the trial data (cumulative treatment effect) was "moving" over the good area. When the test data "moves" in the optimistic region, the test is promising, but not good enough and more samples may be needed. The number of samples will be automatically re-estimated. When the test data "moves" in the bad area, the test has not been considered invalid; however, this weaker trend may require an unsuspecting effort (number of unsuspecting samples) to succeed in the clinical trial; when the test data "moves" over the null area, the test must be null and can be terminated to avoid unscrupulous patient distress and unnecessary economic waste.

Disclosure of Invention

In one aspect, the present invention provides a calculator-based radar system and method for monitoring and directing a clinical trial in progress on a tunable and dynamic basis.

In one embodiment, a radar system includes a clinical trial database, a therapy database, a Dynamic Trial Design (DTD) module, a Dynamic Data Monitoring (DDM) engine, a trial simulation engine, a parameter input interface, and a trial radar display screen. In one embodiment, the graphical user interface includes a parameter input interface and a display screen. In one embodiment, a clinical trial database stores patient information from an on-the-fly clinical trial, wherein the information includes a set of subject data that is continuously updated as the on-the-fly clinical trial progresses. In one embodiment, the treatment database stores treatment assignments (typically random assignments) for patients. In one embodiment, the clinical trials database and the treatment database are systematically integrated. In one embodiment, the DTD module divides the trial data space into four regions based on initial design parameters: good, optimistic, bad (or, bad), and invalid areas. In one embodiment, the boundaries of these regions may be further adjusted when the assumptions are modified or during the performance of a clinical trial. Design parameters typically include, but are not limited to, the following: the assumed therapeutic effect, the overall required diagnostic power, the maximum number of samples willing to be taken, whether considering an early cessation based on efficacy or ineffectiveness. The boundaries of the created area are calculated from the initial design parameters. In one embodiment, the DDM engine performs a series of user-specified tasks as the patient data accumulates. These tasks include, but are not limited to, the following:

a. the cumulative treatment effect (efficacy or safety) is calculated.

b. The CP is calculated based on the assumptions selected by the user.

c. According to the current trend, calculating the comparison initial sample number N ₀ The ratio of the number of samples (R).

d. The linearity of the cumulative treatment effect data is evaluated.

e. The initial assumptions are modified, if necessary.

f. The regions and boundaries are updated according to the modified assumptions.

g. A "weighted" trend score of the cumulative patient data is calculated.

h. A "weighted" treatment trajectory is predicted from the accumulated patient data.

In one embodiment, the simulation engine performs the simulation (at least 1000 times) by adjusting various parameters to evaluate the reliability (or confidence interval) of the trends and trajectories. In one embodiment, the test radar screen displays four zones, a stopping boundary, cumulative treatment effect (efficacy or safety), trends, and treatment trajectories. In one embodiment, the DDM engine performs the task on a particular subset of patients.

Definitions and abbreviations:

in one embodiment, the present invention provides the following data monitoring guidelines: let t _k And d _k The analysis time point and the stopping border in the kth phase, respectively, K =1,2, \8230, K = final point. One guide in DDM to monitor the running test and need to know that K is only for planning purposes and not a fixed number.

(1) If Z (t) _k )≥d _k Or

Stopping the test in advance to gain benefits;

(2) If B (t) _k ) Continuing to fall into the "null" region, we can consider stopping the null trial. However, the ineffective decision is not binding.

(3) Between (1) and (2) above, monitoring is continued with or without any modification in view of SSR:

a) If CP (t) _k ) Not less than 1-beta or, equivalently

But not more than

I.e. in the "good" region, it remains unchanged;

b) If gamma (t) _k ,R _max )≤CP(t _k )<1-beta (i.e. B (t)) _k ) Falls in the "optimistic" region), the experiment should be continued. If we observe consecutive m (e.g., 10) points in the region, the SS is re-evaluated. R _max The choice of (a) depends on the client's burden capacity. For example, if acceptable, set R _max And =3. Future boundary values are also recalculated as SS increases.

c) If B (t) _k ) Falling in the "bad" area, we will not take any decision/action, but continue the monitoring. If B (t) stays in the area all the time, it may be advisable to terminate the trial for administrative reasons, such as exceeding an affordable budget.

Drawings

FIGS. 1A and 1B show snapshots and a continuous display of data, respectively, of the Wald statistic during interim analysis.

Figure 2 shows the non-linear trend of the data.

FIG. 3A is a radar system icon between Z-value and information score that divides the trial data space into four regions, namely good, optimistic (promising), bad (bad) and invalid regions. FIG. 3B is a radar system icon between B-value and information score that divides the trial data space into four regions, namely good, optimistic (promising), adverse (bad), and invalid regions.

Fig. 4A shows a schematic diagram of a system comprising a clinical trial database, a processing unit and a decision unit, wherein the processing unit comprises a decryption module, a simulation module and a statistics module. FIG. 4B shows a typical system comprising DTDs, DDMs and a simulation engine, and how they interact with a database. Fig. 4C shows the creation of a boundary by the DTD module based on design parameters. Figure 4D shows data monitoring a clinical trial in progress. Fig. 4E shows the use of simulations in the monitoring. Fig. 4F is a typical workflow showing how to dynamically monitor a clinical trial and how to suggest a clinical trial. FIG. 4G illustrates a typical radar system, which includes a boundary determination module, a boundary adjustment module, and a display module. FIG. 4H is a schematic diagram of a Graphical User Interface (GUI) with adjustable boundaries.

Fig. 5A shows the borderlines of the good and optimistic areas. Fig. 5B shows the lower limit of CP in the optimistic region. As shown in the figure, R _max The larger the "optimistic" region will be the lower the borderline or the larger the "optimistic" region will be.

Fig. 6A and 6B show the Z and B values, respectively, of the effect of treatment monitored on day 28 as patient data is accumulated on the radar screen. Figure 6C shows the CP monitored on day 28 as patient data accumulates on the DDM radar screen.

Figure 7A is the Z and B values monitored by applying DDM retrospectively to the real, positive clinical trial in example 2. Figure 7B is the CP monitored in the real, positive clinical trial in example 2.

Figures 8A and 8B are Z and B values, respectively, monitored by retrospective application of DDM to real, negative clinical trials in example 3.

Figure 9 shows the patient response rates to placebo (left) and reed-ciclovir (right) in a real clinical trial.

Figure 10A shows a Graphical User Interface (GUI) diagram of the parameter design time of the DTD module. FIG. 10B is a representative table summarizing all parameters on the GUI for dynamic design. Fig. 10C (left panel) shows three (3) regions according to the boundary parameters and a graph based on the simulation. Fig. 10C (right panel) shows the prediction results of the early efficacy boundary.

FIG. 11A shows a GUI schematic for dynamic monitoring during a clinical trial. Fig. 11B shows a panel for interfacing and communicating with patient data. FIG. 11C shows an exemplary table summarizing all parameters on the GUI for dynamic monitoring. Fig. 11D shows three regions according to boundary parameters and a graph based on accumulated patient data.

Detailed Description

In one aspect, the present invention provides a decision making system to manage or monitor an ongoing clinical trial. In one embodiment, as shown in FIG. 4A, the system includes: 1) A clinical trial database for storing information relating to the on-the-fly clinical trial; 2) A processing unit coupled to the clinical trial database; and 3) a decision unit.

In one embodiment, the information comprises a set of subject data that is encrypted and continuously updated, wherein the set of subject data comprises a set of control data and a set of experimental data. In one embodiment, a processing unit comprises: a) A decryption module for decrypting the set of subject data to identify the set of experimental data; b) A simulation module to generate a set of simulation data based on the set of experimental data; and c) a statistics module for calculating one or more scores reflecting the probability of success of the on-the-fly double-blind clinical trial, wherein the one or more scores are calculated based on the set of experimental data or the set of simulation data and a set of criteria selected from the group consisting of good criteria, bad criteria and promising criteria.

In one embodiment, the decision unit is coupled to a clinical trial database and comprises: a) A scoring module to display the one or more scores associated with a double-blind clinical trial in operation; b) An options module to display one or more options for the user to manage the on-the-fly clinical trial, wherein the one or more options are fed back to the simulation module to adjust the set of simulation data or the set of criteria and update the one or more scores.

In one embodiment, the present invention provides a radar system having four zones as a monitoring interface for monitoring and directing a test in operation. As shown in fig. 3A and 3B, these four regions are good, optimistic (promising), unfavorable (bad), and invalid regions.

Good area

For simplicity, let us temporarily focus on the fixed design, i.e. C _α ＝Z _α . This discussion can be easily extended to cluster-successive designs. In monitoring an ongoing trial, we first evaluate whether the CP at the current "snapshot" is greater than 1- β (e.g., 90%). In other words whether or not

Derived from formula (1) and

into theta, i.e.

According to the classification of Mehta and Pocock (2011) { B (t) ≧ B ₁ (t, 1-beta) } area is considered "good" [25 ]]。b ₁ (t, 1-. Beta.) is the boundary line between the good area and the optimistic area. In this example (fig. 3A and 3B, α = 0.025), it is also possible to include a selected discrete boundary of the rejection zone (depending on the schedule), and to use a O' Brien-Fleming (OBF) -type continuous monitoring boundary (B (t) = 2.24), which is located at the top of the extreme rejection zone.

Optimistic and bad area

Mathematically, the domain of brownian motion B (t) may exceed 1. Let N be ₀ The number of raw samples per group was chosen to meet the unconditional assay force requirement of 1-beta'. The adaptive process allows for any time (e.g., at t = N/N) ₀ Case) changes the SS using the observed B (t). Assume a new number of samples per group of N ₁ >N ₀ Corresponding to the information time T ₁ ＝N ₁ /N ₀ . Let B (T) ₁ ) Is T ₁ Potential observations of time. In order to maintain the error rate of the first type, the critical boundary C must be set _α ＝C ₀ Is adjusted to C ₁ Then P (B (T) can be obtained under the condition of no virtual hypothesis ₁ )≥C ₁ |B(t))＝P(B(1)≥C _α | B (t)). Independent incremental nature of brownian motion gives

Solving for C ₁ The following equation is generated for the new threshold value:

using the same method of deriving (1) and (2), B (t) -based extended CP is given:

set it to 1-beta and substitute C from equation (3) ₁ We get

T ₁ ＝N ₁ /N ₀ Is a new sample number ratio that satisfies the conditional assay force 1-beta (in general, we can set 1-beta = 1-beta').

In designing the trial, we may wish to control the ratio of sample numbers not to exceed the maximum affordable budget. Let R _max Is the maximum sample number ratio considered. From equation (4), the ratio R of the number of samples at a given desired CP can be expressed as

According to a given R _max Solving for B (t) results in the following inequality,

show that

Inequality (5) results at a given R _max "optimistic" area represented by B value: b ₂ (t,R _max )≤B(t)≤b ₁ (t, 1-. Beta.). In the "optimistic" region, the maximum sample number ratio is set to be not more than R _max . Note that CP under the current "snapshot" is

By using

Substituting B (t)/t, we map the conditional power in the "optimistic" region, hence

This gives another expression for the "optimistic" region, denoted CP. To keep in mind that R is _max The lower limit defined is a decreasing function of t, consisting of

To

Note that when B (t) falls in the "optimistic" region, γ (1,R) _max ) Is the CP worst case. While monitoring an ongoing test, we may wish to choose that CP is not too low (e.g.<20%) for SSR. Thus, γ (t, R) _max ) Can be used to select an interim analysis time or a time interval that takes into account SSR.

Fig. 5A and 5B show the "good" and "optimistic" regions, respectively, and the lower bound of the CP. In FIG. 5B, B (t) falls within the "optimistic" region, the target CP is 1- β and R _max =1.5, 2.0, 3.0 and 4.0. In FIG. 5A, the "good" area is above the top line, and "The optimistic region lies on the line and corresponds to a different R _max Between the other lines. As shown in FIG. 5A, R _max The larger the "optimistic" region will be the lower the borderline or the larger the "optimistic" region will be. Fig. 5B shows the lower bound of the CP, which also forms the corresponding "optimistic" region denoted by CP. For example, when R _max When =2.0, the lower limit of the CP is in the range of 0.630 (t = 0) to 0.248 (t = 1).

Region B (t) in FIG. 3<b ₂ (R _max T) are temporarily referred to as "bad" areas (just because they are located below the "optimistic" area). Since the CP of the boundary line ranges from 0.630 (t = 0) to 0.248 (t = 1), it is readily seen that we may not wish to terminate the test prematurely even in the "bad" areas. We need to further define the "invalid" region to account for the possibility of premature termination.

Ineffectiveness is also often monitored during the course of the test, either alone or sometimes embedded in the life cycle analysis. In both cases, the invalidity analysis plan is not applied to the control for modifying the error rate of the first type, since the decision to stop the trial, whether or not the trial is invalid, is not binding. In contrast, analysis during the null period increases the error rate of type two, resulting in a decrease in the assay force of the study. The ineffectiveness analysis needs to take into account the assay force problem. Frequent invalidating analyses may result in excessive assay force loss.

How much assay force loss will result from the ineffectiveness of the continuous monitoring test? If the ineffectiveness is monitored by the conditional power of Check (CP) (random reduction) method, the answer is in Lan, simon and Halperin (1982) [26]Is given in (1). We are at H _a Using θ in the case of ^* ＝Z _α +Z _β′ Instead of the current estimate

The conditions of (1). When CP (based on theta) ^* ) Below a threshold value (gamma) _f ) Then the test is deemed invalid and may be stopped by invalidity. Therefore, we construct a continuous invalid region represented by the value B:

see the defective area in fig. 3. The maximum assay force loss compared to the original assay force 1-beta' is

For example, if the design verification force is 0.9 and γ _f Below 0.5, we can expect the loss to be not more than 0.1. A final (unconditional) assay force equal to 0.8 may be considered acceptable. For gamma _f =0.20, assay force loss as low as 0.025. Gamma ray _f The lower the assay force loss. In general, with a uniform threshold γ _f The loss of assay force is negligible.

In practice, CP (t) will be checked _i )<γ _i I =1,2, \ 8230k, k, in a predetermined interim time t _i Occasional invalidity analyses were performed. Unlike the invalidity rule which applies uniformly to the continuous boundaries of all t, we can see at t _i Tolerance of CP, γ, to be accepted _i The selection of (b) may be flexible. For example, we can select a smaller γ at an earlier point in time than at a later point in time _i To avoid premature ineffective cessation. In view of when to perform the ineffectiveness analysis, it is desirable that the procedure be able to detect ineffectiveness as quickly as possible to save costs and reduce the pain to humans due to ineffective treatment. On the other hand, early ineffectiveness analysis is more likely to result in loss of detectability for effective treatment. Therefore, we can tailor the time problem of the invalidity analysis to be an optimization problem by seeking to minimize the number of samples (cost) while controlling the assay force loss. This method developed by Xi, gallo and Ohlssen (2017) (27) is implemented in DDM.

Note that "bad" areas are neither hoped nor invalid. In other words, in this region, due to R>R _max An increase in SS is not feasible, but the study cannot be considered ineffectiveIn (H) _a In case of (2) CP>γ _f ). The effect is still positive (Z value or B value)>0). In this case we will not make any decision/action, but continue the monitoring.

To summarize, let t _k And d _k The analysis time point and the stopping border in the kth phase, respectively, K =1,2, \8230, K = final point. We developed a guide in DDM for monitoring the ongoing experiments and needed to understand that K is only used for planning purposes, not a fixed number.

(1) If Z (t) _k )≥d _k Or

Stopping the test in advance to obtain benefits;

(2) If B (t) _k ) Continuing to fall into the "null" region, we can consider the trial to stop null. However, the ineffective decision is not binding.

a) If CP (t) _k ) Not less than 1-beta or, equivalently

But not more than

I.e. in the "good" region, it remains unchanged;

b) If gamma (t) _k ,R _max )≤CP(t _k )<1-beta (i.e. B (t)) _k ) Falls in the "optimistic" region), the test should be continued. If we observe consecutive m (e.g., 10) points in the region, the SS is re-evaluated. R is _max The choice of (c) depends on the client's burden capability. For example, if acceptable, set R _max And =3. Future boundary values are also recalculated as SS increases.

c) If B (t) _k ) Falling in the "bad" area, we will not take any decision/action, but continue the monitoring. If B (t) stays at all timesThis area, then, may be recommended for administrative reasons, such as exceeding an affordable budget, to terminate the trial.

In one aspect, the present invention provides a radar system to dynamically monitor a clinical trial and adapt to boundaries as the clinical trial progresses. In one embodiment, the radar system adjusts the zone boundaries by adjusting boundary parameters and/or clinical trial parameters. In one embodiment, the present invention provides a Graphical User Interface (GUI) to monitor clinical trials based on adjustable boundaries. As a typical example, FIG. 11A shows a GUI with parameters for monitoring, FIG. 11B is an interface for interfacing with a database and data collection, FIG. 11C is a summary table listing all parameters corresponding to the monitored boundaries in FIG. 11D with three main regions. Fig. 11D also shows a graph based on the accumulated data. In one embodiment, the boundary parameters include, but are not limited to, CP, B value, Z value, type one or type two errors.

In one embodiment, the boundary parameters are set to stay consistent with the target in a particular phase. For example, new sample numbers and N may be continuously calculated ₀ And is used to show the number of new samples, e.g. 95%, that achieve the required conditional verification force (CP). In one embodiment, R may be closely monitored such that it does not exceed a maximum affordable budget (e.g., a maximum sample number ratio (R) corresponding to the maximum affordable budget _max )). In one embodiment, R _max Depending on the stage in which it is located and the target value (e.g., CP) of the statistical pointer. In one embodiment, the required CP may be a fixed value, as shown in Table 2-1. When t is less than 0.2, R _max May be as high as 10 to avoid missing any chance due to insufficient data; and when the clinical trial is about to be completed, i.e. R _max Only up to 1.5. In one embodiment, the required CP may be phase-specific, as shown in Table 2-2. For example, at the beginning (t)<0.2 Required CP may be as low as 20%, R) _max Possibly up to 15. However, when it is 0.9<t<1.0, R is complete because most of the data is complete _max Only 1.2 can be reached to achieve 90% of the target CP. In one embodiment, the clinicThe test can be divided into 2 to 10 stages.

_max TABLE 2-1 dependence of R on time at fixed CP

	t<0.2	0.2<t<0.4	0.4<t<0.6	0.6<t<0.8	0.8<t<0.9	0.9<t<1.0
							R _max	10	7.5	5.5	3.0	2.0	1.5

_max TABLE 2-2 dependence of R on time and phase-specific CP

t<0.2

0.2<t<0.4

0.4<t<0.6

0.6<t<0.8

0.8<t<0.9

0.9<t<1.0

R

_max

15

10

7.0

3.0

1.5

1.2

CP

20％

50％

70％

80％

85％

90％

In one embodiment, the stage-specific CP depends on the accumulated existing CP. In one embodiment, data trends are also taken into account when estimating the phase-specific CP.

In one embodiment, the user provides the system with phase-specific boundary parameters via an input unit. In one embodiment, the input unit converts a new set of boundary parameters defining a new boundary or input from a user into a set of signals recognizable by a boundary adjustment module that converts the signals into a new set of boundary parameters executable by a boundary determination module through operation with a conversion interface or a graphical user interface. In one embodiment, a program integrated as part of the system, such as a calculator interface programmed with a phase-specific CP, updates phase-specific boundary parameters upon request.

In one embodiment, the present invention provides a radar system for monitoring an ongoing test in a DDM. In one embodiment, the radar system classifies the entire image into three regions, namely, a bad region, an optimistic region, and a good region. In one embodiment, the defective area includes an invalid area. In one embodiment, the good area comprises a success area. In one embodiment, the disclosed system also provides recommendations based on the region in which the clinical trial is located. In one embodiment, the boundary is determined by a Z value or a B value.

After updating or collecting new clinical trial data, the DDM engine (radar system) evaluates the accumulated clinical trial and step 1 determines whether the clinical trial falls into a success zone or an invalid zone, as shown in fig. 4F. If so, an early termination suggestion should be provided for success or ineffectiveness. Otherwise, i.e. it does not belong to both regions, it should be determined in step 2 how to proceed. If it falls into a good area, the clinical trial can be continued without any modification; if it falls within the optimistic region, clinical trial parameter adjustments (e.g., SSR) may be made before continuing to perform the clinical trial; if it falls into a poor area, and if step 3 determines that there is an opportunity to escalate to a better area with an affordable SS, the clinical trial may proceed cautiously. If step 3 determines that there is no opportunity to upgrade to a better area with affordable SSs, the clinical trial may be terminated for administrative reasons. In one embodiment, the present invention provides a method of monitoring a clinical trial using a radar system. In one embodiment, the DDM engine operates with Dynamic Trial Design (DTD) for hypothesis-based initial clinical trial design. For example, DTD may estimate initial SS based on a) required values for significance level and assay force, and b) assumed values for some parameters (e.g., treatment effect). In one embodiment, the DDM engine operates with a simulation engine that simulates and predicts future trends and trajectories of the clinical trial based on the accumulated data.

Assuming that a test divided into two groups was designed, the ratio of experimental therapy to standard therapy was 1:1. assuming a therapeutic effect of 0.4, the design assay force was 1- β =0.9 and α =0.025 (single tail). Thus, the initial SS of each group is N =132. Upper limit of SS (N) of each group _cap ) Is set to 600 (i.e. R) _max = 4.5) and starts monitoring at t =0.4. The required CP is set to 0.9. Thus, the good and optimistic regions are bounded by the boundary line

And

and (4) constructing. For invalidity, continuous invalid boundary

According to gamma _f Case constructions of =0.05, 0.10, 0.15 and 0.20.

OB-F type boundaries were also used for early efficacy-based stopping with 5 observations (4 phase neutrality and one final) at equal distances (t =0.2, 0.4, 0.6, 0.8, 1). After t =0.4, it is used here only for monitoring the SS ratio (R) and the invalidity (0.4, 0.55, 0.70, 0.85). In the simulation, the following procedure was adjusted.

1) If m consecutive points (e.g., 10) of the accumulated data (e.g., B value) fall within the optimistic region, the SS is adjusted

Will be executed only once and a new final critical boundary is calculated according to equation (3);

2) If B (t) is too small

It is called invalid.

TABLE 3 simulation of Radar System with dynamic and adaptive functionality

Note that: simulation number =100,000, monitoring starts at t =0.4. If SSR or invalid stop or power stop is not performed, the time point is set to 1, respectively.

As can be seen by the simulation (table 3):

1) The error rate of the first type is well controlled;

2) When delta _tue If =0, the invalid state is detected at a relatively early stage (0.59 to 0.68), and the detection rate is determined>85％；

3) When delta _tue >At 0, the actual detection force is slightly larger than the target detection force corresponding to each group of N =132 because the built-in SSR has no detection force loss;

4) When the therapeutic effect is over-postulated (delta) _tue = 0.25), SSR averaging is performed around t = 0.81. If the therapeutic effect is assumed correctly (delta) _tue = 0.40), then efficacy can be said to be in the early stages around t = 0.79.

The above simulations show that a radar system with dynamic and adaptive functions works well at a given setting.

Using radar systems through DMC

In most phase II-III clinical trials, the Data Monitoring Committee (DMC) regularly monitors safety and/or efficacy and, depending on the disease and specific intervention, is usually prescribed every 3 to 6 months. For example, DMC may be opened more frequently at an early stage to gain a faster understanding of safety, or DMC may be opened more frequently for oncology trials with new therapies than trials for non-life threatening diseases. Current practice of DMC involves three parties: the delegator, independent Statistical Group (ISG) and DMC. The delegator will perform and manage the ongoing study. The ISG prepares blind data and blinded packets according to the planned data cutoff date (usually one or more months before the DMC conference): tables, lists and graphs (TLF). The preparation is usually time consuming, taking about 3 to 6 months. Conventional DMC practices have several disadvantages. First, the data packets analyzed at each session reflect only a snapshot of the data and cannot show trends in the efficacy (efficacy or safety) of the treatment. Second, the blinding of the data and the preparation of the data packets are very time consuming. Typically, the ISG takes approximately 3 to 6 months to unblind the data and prepare the data packet for review by the DMC. Human participation can lead to errors.

In another important aspect, the radar system of the present invention is used for emergency testing in a pandemic crisis such as COVID-19. Monitoring results (e.g., safety and efficacy) and adjusting clinical trials in a near continuous and timely manner is highly desirable and challenging. As mentioned above, conventional approaches sacrifice life and expend a lot of budget due to inefficiency and lack of flexibility. In one embodiment, a radar system with dynamic and adaptive functionality can collect, blindly resolve, and analyze data in real-time and, based on the accumulated data, provide timely advice on how to manage or adjust a clinical trial.

This degree of usability is necessary for the Data and Security Monitoring Committee (DSMC) to effectively perform its function. In the tenth meeting held by doctor Janet Wittes in 2018 at university of pennsylvania [28], all data, not just certain variables, must be provided to an independent statistician at all times, not just before the meeting. The radar system and detection method of the present invention can be directly applied to DSMC. This application does not affect the performance of clinical trials, nor does it affect the independence of data monitoring or analysis. By integrating with the EDC/IWRS system, the radar system can create a seamless data monitoring ecosystem. In one embodiment, the present invention may use predetermined parameters (e.g., efficacy and/or null boundaries) and status regions (as described above) to construct a test radar system. In one embodiment, the present invention may use the then specified parameters (e.g., efficacy and/or invalidity bounds) and status regions (as described above) to construct the regions/bounds. In one embodiment, the parameters specified at the time are determined based on the clinical trial data and guidelines, such as the maximum budget, available at the time. In one embodiment, the cumulative experimental data of interest (e.g., efficacy and safety) may be displayed via a display module or graphical user interface associated with the radar system. In one embodiment, the radar system not only suggests continuation/non-continuation in interim analysis, but also provides guidance in real time to reach its final destination. In one embodiment, to minimize potential operational variances, the radar system allows data access with authorization via the authorization module. In one embodiment, only DSMC members have access to the radar system through encryption. In one embodiment, the radar system only presents results at a specified time, such as a DSMC conference. In one embodiment, for the purpose of closely monitoring drug safety, the DSMC may need to turn on only the display of the safety portion in order to monitor it directly in real time.

In one embodiment, the radar system of the present invention may be used in the following applications:

■ And (5) performing test diagnosis. Radar systems can be retroactively used in research studies to understand what happens during the trial and what is critical to the final result. This may apply to all types of studies, including those that failed. Please refer to the example.

■ And (5) detecting the safety of the medicine. Radar systems can continuously monitor the safety of drugs or drug candidates and detect signals.

■ And (4) selecting dosage. By identifying the dose with the greatest potential for phase III, the radar system can be used for seamless, optimal phase II/III combinatorial testing.

■ And (4) selecting the crowd. The radar system can identify the most effective subpopulation of drugs and apply directly to the RCT or RWE settings for personalized medicine.

In one embodiment, the present invention provides a graphical user interface based system for monitoring and directing a clinical trial in progress on a tunable and real-time basis, comprising:

a. a clinical trial database for storing information for an on-the-fly clinical trial, wherein the information comprises a set of subject data that is continuously updated as the on-the-fly clinical trial progresses;

b. a boundary determination module for determining a boundary of a set of regions comprising a good region, an optimistic region and a bad region, wherein the boundary is adjustable as the on-the-fly clinical trial progresses, wherein each region represents a different risk level associated with the cumulative effects of the on-the-fly clinical trial; and

c. a Graphical User Interface (GUI) operable with the boundary determination module for displaying a graph of the cumulative effect of the on-the-fly clinical trial and boundary parameters corresponding to the set of zones, wherein the GUI allows a user to adjust values of boundary parameters based on the graph, thereby generating new boundaries in real-time as the on-the-fly clinical trial develops, wherein the cumulative effect of the on-the-fly clinical trial is continuously projected onto the graph, thereby monitoring and guiding the on-the-fly clinical trial on a tuneable and real-time basis.

In one embodiment, the set of subject data includes blinding data or one or more cumulative effects derived from said blinding data.

In one embodiment, the bad area comprises an invalid area and the good area comprises a successful area.

In one embodiment, the GUI provides recommendations based on the region in which the on-the-fly clinical trial is located, wherein the recommendations are:

a. "terminate early due to success" if the cumulative effect falls within the success region;

b. "terminate early due to invalidation" if the cumulative effect falls in the invalidation region;

c. if the cumulative effect falls in the good region but not the successful region, "continue without modification";

d. "continue after sample number re-estimation" if the cumulative effect falls within the optimistic region; or

e. If the cumulative effect falls in the bad area but is not a null area, then "proceed cautiously".

In one embodiment, the cumulative effect is one or more statistical scores selected from the group consisting of: score statistic (B value), wald statistic (Z value), point estimation

And a 95% confidence interval, a conditional verification force (CP), a first type error, and a second type error.

In one embodiment, the boundary parameter has an ideal value that is phase or time specific.

In one embodiment, the system operates with a simulation module that simulates in view of accumulated trends for the set of subject data and the graph thereof, predicts future trends and trajectories of the on-the-fly clinical trial, and optionally by comparison with an initial or existing clinical trial design and assumptions for the initial or existing clinical trial design, to suggest clinical trial parameter adjustments.

In one embodiment, the simulation is performed by trend analysis.

In one embodiment, the trend analysis is a piecewise linear analysis in which different weights are assigned to each segment that exhibits a linear trend.

In one embodiment, the good region corresponds to a B value of not less than B ₁ (t, 1-. Beta.) region; optimistic region corresponding to B value not greater than B ₁ (t, 1-. Beta.) but not less than b ₂ (t,R _max ) The area of (a); and the defective region corresponding to B value less than B ₂ (t,R _max ) The area of (a); wherein said R _max Is the maximum sample number ratio of the on-the-fly clinical trial at time t.

In one embodiment, the invalid region corresponds to a B value no greater than B _f (t) in which b _f (t) is a threshold value representing an invalid conclusion with a significant difference at time t, and the success region corresponds to a region where the B value is not less than Cs, where Cs is the threshold value representing a successful conclusion with a significant difference。

In one embodiment, a set of regions in the graph are marked with different colors or patterns.

In one embodiment, when the on-the-fly clinical trial continuously falls within the optimistic region for 10 points, the system provides a signal indicating a need to adjust one or more clinical trial parameters of the on-the-fly clinical trial.

In one embodiment, the present invention provides a graphical user interface based method for monitoring and directing a clinical trial in progress on a tunable and real-time basis, comprising:

a. storing information for an on-the-fly clinical trial in a clinical trial database, wherein the information comprises a set of subject data that is continuously updated as the on-the-fly clinical trial progresses;

b. mapping, by a boundary determination module, boundaries of a set of regions including a good region, an optimistic region and a bad region, wherein the boundaries are adjustable as the in-flight clinical trial progresses, wherein each region represents a different risk level associated with cumulative effects of the in-flight clinical trial;

c. performing the boundary adjustment on a Graphical User Interface (GUI), wherein the GUI displays a graph of the cumulative effect of the on-the-fly clinical trial and boundary parameters corresponding to the set of regions, the GUI allowing a user to adjust the values of the boundary parameters based on the graph, thereby generating new boundaries in real-time as the on-the-fly clinical trial progresses, wherein the cumulative effect of the on-the-fly clinical trial is projected continuously onto the graph; and

d. providing, via the GUI, a recommendation that directs the clinical trial in progress, wherein the recommendation is based on the area in which the clinical trial in progress is located

1) "terminate early due to success" if the cumulative effect falls within the success region;

2) "terminate early due to invalidation" if the cumulative effect falls within the invalidation region;

3) If the cumulative effect falls in the good region but not the successful region, "continue without modification";

4) "continue after sample number re-estimation" if the cumulative effect falls within the optimistic region; or

5) If the cumulative effect falls within the bad area but is not a null area, "proceed cautiously".

In one embodiment, the present invention provides a graphical user interface based method for diagnosing a completed clinical trial comprising:

a. sequentially applying information in completed clinical trials to a clinical trial database according to the time of completion of the patient data, wherein the information comprises a set of subject data that is continually updated;

b. mapping, by a boundary determination module, boundaries of a set of regions including a good region, an optimistic region and a bad region, the boundaries being adjustable in applying the information, wherein each region represents a different risk level associated with cumulative effects of the on-the-fly clinical trial;

c. performing the boundary adjustment on a Graphical User Interface (GUI), wherein the GUI displays a graph of the cumulative effect of the clinical trial on the fly and boundary parameters corresponding to the set of regions, the GUI allowing a user to adjust the values of the boundary parameters based on the graph, thereby generating a new boundary based on the assumption that the clinical trial is on the fly, wherein the cumulative effect of the clinical trial is projected continuously onto the graph; and

d. providing, via the GUI, a diagnosis of the clinical trial, wherein the diagnosis is based on the region in which the clinical trial is located, assuming that the clinical trial is in operation

In one embodiment, the present invention provides a radar system for monitoring and directing an ongoing clinical trial on a tunable and real-time basis, comprising:

b. a boundary determination module for determining a boundary of a set of regions including a good region, an optimistic region and a bad region, wherein the boundary is adjustable as the in-flight clinical trial progresses, wherein each region represents a different risk level associated with cumulative effects of the in-flight clinical trial;

c. an interactive boundary adjustment module, operable with said boundary determination module, for adjusting an existing boundary to a new boundary based on said graph in real time as said on-the-fly clinical trial develops; and

d. a display module for continuously projecting said cumulative effect of said on-the-fly clinical trial onto a graph comprising said set of regions, thereby monitoring and guiding said on-the-fly clinical trial on a tunable and real-time basis.

5) If the cumulative effect falls in the bad area but is not a null area, then "proceed cautiously".

In one embodiment, based on the graph, the boundary adjustment module adjusts an existing boundary to a new boundary by converting a new guide into a set of new boundary parameters that define the new boundary.

In one embodiment, the set of new boundary parameters reflects ideal values that are phase or time specific.

In one embodiment, the radar system operates with a simulation module that simulates in view of accumulated trends for the set of subject data and the graph thereof, predicts future trends and trajectories for the on-the-fly clinical trial, and optionally by comparison with an initial or existing clinical trial design and assumptions for the initial or existing clinical trial design, to suggest clinical trial parameter adjustments.

In one embodiment, the simulation is performed by trend analysis.

In one embodiment, the trend analysis is a piecewise linear analysis in which a different weight is assigned to each segment that exhibits a linear trend.

In one embodiment, the good region corresponds to a B value of not less than B ₁ (t, 1-. Beta.) region; optimistic region corresponds to B value less than B ₁ (t, 1-. Beta.) but not less than b ₂ (t,R _max ) The area of (a); and the defective region corresponding to the B value being less than B ₂ (t,R _max ) The area of (a); wherein said R _max Is the maximum sample number ratio of the on-the-fly clinical trial at time t.

In one embodiment, the invalid region corresponds to a B value no greater than B _f (t) region of (t) wherein b _f (t) is a threshold value representing invalid conclusions with significant differences at time t, and the success region corresponds to a region where the B value is not less than Cs, where Cs is a threshold value representing successful conclusions with significant differences.

In one embodiment, when the on-the-fly clinical trial continuously falls within the optimistic region for 10 points, the radar system provides a signal indicating a need to adjust one or more clinical trial parameters of the on-the-fly clinical trial.

In one embodiment, the present invention provides a method for monitoring and directing an ongoing clinical trial on a tunable and real-time basis, comprising:

b. mapping, by a boundary determination module, boundaries of a set of regions including good regions, optimistic regions and bad regions, wherein the boundaries are adjustable as the on-the-fly clinical trial progresses, wherein each region represents a different level of risk associated with cumulative effects of the on-the-fly clinical trial;

c. performing, by an interactive boundary adjustment module, the boundary adjustment to adjust values of the boundary parameters according to the graph to generate new boundaries in real-time as the on-the-fly clinical trial develops;

d. continuously projecting, by a display module, the cumulative effect of the on-the-fly clinical trial onto a graph comprising the set of regions; and

e. providing, by the display module, a recommendation that directs the clinical trial in progress, wherein, depending on the zone in which the clinical trial in progress is located, the recommendation is:

2) "terminate early due to invalidation" if the cumulative effect falls in the invalidation region;

3) If the cumulative effect falls in the good region but not the success region, "continue without modification";

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The present invention will be better understood by reference to the following experimental details, but it will be understood by those skilled in the art that the detailed experiments are illustrative only and should not limit the invention described herein, which is defined by the claims that follow.

In the application, various references or publications are cited. The entire disclosures of these references or publications are incorporated herein by reference in order to more fully describe the state of the art to which this invention pertains. It should be noted that the terms "comprising," "including," and the like, when referred to as synonyms, are intended to be open-ended and do not exclude other unrecited elements or method steps.

EXAMPLE 1 use of the Radar System in the first clinical trial of Reidesciclovir on critically ill CoVID-19 adult patients

The first double-blind, placebo-controlled clinical trial was conducted in Wuhan, china during months 1-3 in 2020, and the potential antiviral effects of Reidesciclovir in critically ill COVID-19 adult patients was studied (Wang et al, 2020) [29]]. During a pandemic crisis, the trial is monitored globally and the DMC of the trial is commissioned to make a quick and scientifically sound decision. DMC faces a great challenge to be very efficient and timely in data transmission and monitoring of critical efficacy and security data. DMC decisions on the use of eDMC as a result of the patient's prompt enrollment in clinical trials ^TM Software (CIMS Global) and our DDM "test Radar" to monitor continuous critical safety and efficacy data (Shih, yao) almost weekly&Xie，2020)[30]. The key efficacy endpoint for DMC program monitoring is the 6-point ranking score of the clinical condition of patients on

days

7, 14, 21, and 28. (however, at early review meetings, the DMC also required real-time viewing of

day

3, 5, and 10 data, which was characterized as exploratory.)

The rank scale distribution of the different treatment groups was compared using a stratified sampling Wilcoxon-Mann-Whitley (WMW) rank-sum test according to the DMC chapter program. As the trial progresses, and also as the patients accumulate and the treatment time increases, the trend of the test is monitored. The distribution data is displayed by bar chart and WMW rank and check is tracked on DDM "radar" screen. The "radar" screen is composed of CP areas to display rank and check whether it is in "good", "optimistic", "bad" or "invalid" areas. The track of the rank sum test indicates the trend of the test results detected as patients are enrolled from time to time. As expected, more data was collected early in the trial, and less data was collected at follow-up on subsequent days. Thus, the data check is exploratory. Only when the rank-sum test shows a stable strong signal (i.e. falls within a good area) will the formal analysis of the primary endpoint of the planned design be triggered, i.e. the Time To Clinical Improvement (TTCI). Followed byOver time, more patients had longer follow-up data as expected. Exploratory analysis is usually performed on a plan by examining the "radar" map. However, if it is desired to prevent the false positive rate from being too high, especially in the later stages of the trial, when a sufficient number of patients are enrolled/followed and will be checked for multiple rank-sum tests on

days

7, 14, 21 and 28, the DMC program uses the Hochberg stepwise analysis to protect the overall alpha of this order (secondary) endpoint at a level of 0.025 (single-tailed, or double-tailed 0.05). Since it is not known when and how many times the TTCI analysis will be triggered, a cluster-successive flexible alpha consumption function method was designed to keep the overall alpha of the TTCI primary endpoint also at a 0.025 (single-tailed, or double-tailed 0.05) level. Furthermore, given the expected rapid enrollment and the relatively short test period, and given the urgency of the study, the DMC selected the Pocock method alpha consumption function for this primary endpoint. Note that the Pocock method alpha consumption function is concave rather than convex, indicating that an earlier time consumes more alpha than a later time, consistent with an epidemic emergency; see Shih, yao&Xie(2020)[30]. Here, fig. 6A and 6B show WMW rank and Z and B value paths tested at 28 days on DDM "radar" screen at the time around the fifth DMC meeting at around 3 months end of 2020, when 212 patients (of 453 in the plan) completed study treatment and evaluation at day 28. The optimistic region is set at R _max =3, and 1- β =0.90, the CP can satisfy formula (6). The inner dashed-dotted boundary line represents CP =50%.

As shown, on the early DMC meeting, when less than 100 patients (t = 0.22) were evaluated on day 28, the data fluctuated in a good and optimistic area, but after approximately 40 patients (t = 0.088), the CP was most often greater than 50%. DMC felt optimistic and recommended to continue the test. However, CP most of the time drops below 50% and wanders in non-optimistic areas when more patients completed the day 28 assessment. On the fourth DMC session, when day 28 data from about 180 patients was evaluated, the CP was about 33%, thus accounting for the increase in SS. However, since the consignee informed DMC that the pandemic had been controlled in china, the study could not be continued even with the original SS, let alone increased. Due to insufficient enrollment, the study was cancelled at 2 days 4/2020. The usefulness of DDM was fully demonstrated in this test.

Weighted mean trend analysis was performed using 4 piecewise linear drifts in the B-value plots using 4 segments, i.e., t, when 40, 140, 170, and 212 patients completed the trial ₁ ＝0.088、t ₂ ＝0.309、t ₃ =0.375 and t ₄ =0.468. In the B-value graph, the slopes of 4 line segments are respectively

And

we choose to use w ₁ ＝0.05、w ₂ ＝0.30、w ₃ ＝0.30、w ₄ Sensitivity analysis was performed for =0.35, and weighting of the brownian motion model (40/220 =0.18,100/220=0.45,30/220=0.14,50/220= 0.23) was added, and weighting was reduced for an early trend. The resulting weighted average slope is w ₁ S ₁ +w ₂ S ₂ +w ₃ S ₃ +w ₄ S ₄ ＝2.40。

With 2.40 as the estimate of θ in equation (1), the conditional determination force CP (θ, t) =0.469, compare snapshot estimates

And

this sensitivity analysis places the CP in an optimistic region based on the datapath with subjective weighting. Recommendations to increase SS will be made (rather than accepted by the client because of patient scarcity and in this case the pandemic is already under control).

Example 2 application of the Radar System in the diagnostic test of Positive Studies

This is a multicenter, double-blind, placebo-controlled study in which experimental drugs or placebo are administered to nocturnal enuresis patients by oral administration daily over a two-week period. The primary endpoint for this study was a 14-balance average of nocturnal voids. The original design was a fixed sample number design with an 80% assay force when the single tail alpha = 0.025. A total of 83 subjects were randomly assigned to the study. Final analysis showed that the group taking the experimental drug showed significantly better results than the placebo group (Z test compared to 1.96).

We have retroactively reconstructed the study to show the effect of sequential monitoring of patients with the DDM system, depending on the time they completed the 14 day treatment. Fig. 7A and 7B show DDM radar screen graphs and CPs. It can be seen that whether "continuous" or discrete OB-F boundaries (five equally spaced open blue circles) are used, the test does not cross the corresponding boundaries until t >0.85. The potential success rate of this study can be seen from the CP plot: starting from t >0.55, i.e. after completion of the study in 46 subjects, CP was over 80% most of the time. This example also shows that (1) fluctuations occurred during the early stages of the experiment; (2) SSR should not be considered prematurely when the data is still uncertain; (3) At nearly half the time of the study, CP >80%, it is helpful to continue monitoring the experiment; SSR is highly likely not required.

Example 3 use of the Radar System in diagnostic tests for negative Studies

This randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of orally administered experimental drugs in non-alcoholic fatty liver disease (NAFLD) patients. The primary endpoint was the change in serum ALT (glutamate pyruvate transaminase) from baseline to 6 months. 91 subjects were randomized into 3 active (dose) groups and placebo. The original design was a fixed sample number design with an 80% assay force when the single tail alpha = 0.025. Final analysis showed that the active group showed significantly worse results than the placebo group.

Likewise, we retroactively reconstructed the study to show the effect of sequential monitoring of patients with the DDM system according to their time to complete 6 months of treatment. Figures 8A and 8B show DDM screen plots of the combined active group versus placebo along with CP. As shown, from the beginning to the end of the study, the Z values were below zero and the condition-detected force was almost zero. The DDM plot shows that after t =0.40, the trial entered the null region from the non-optimistic region. If DDM is used, the study may be terminated prematurely due to ineffectiveness. One might argue that in such an extreme negative situation there is little need for DDM. However, because of the ineffectiveness and non-binding, snapshot data analyzed in one or more sessions may also fail to convince the delegator to abandon the test unless the path of the data clearly indicates an unexpected trend, which may be provided by the DDM. As described above, clinical trials in poor areas can be continued with caution. If the delegator highly wished to make another attempt at t =0.40, even though the risk was higher than with the current design, the delegator could lower the borderline, temporarily placing the clinical trial in the area of weakness, and thereby recognizing that the clinical trial could proceed with caution. Once the clinical trial re-enters the null area under the new border, it can then decide how to proceed. In one embodiment, the trend of the graph is also taken into account when redefining the boundaries. As shown in fig. 8B, since there is an overall negative trend between t =0 and t =0.35, indicating that there is little chance of returning, the delegator can raise the boundary line of invalidity, and therefore move the position of t =0.35 to the invalid region to indicate that the clinical trial should terminate at t = 0.35.

Example 4 application of the radar System to the first Rudeciclovir test on COVID (example 1) triggers a reanalysis

The first double-blind, placebo-controlled, randomized trial [31] performed in Wuhan, china on patients with severe COVID-19 treated with intravenous Reidcisvir was of high interest. The primary outcome [29] has received global attention. However, after registration of only 237 of the 453 planned patients, the study was stopped early due to patient shortages. The report indicates that no significant difference in benefits of reidesavir was observed, other than those of standard care. This result is in contradiction to the results of a similar test [34] conducted on Reidesciclovir in the United states, first declared by doctor Fauci on 29.4.2020.

The chinese test uses a radar system for monitoring. By looking at the treatment effect plots for the radar system at

days

5, 10, 14, 21 and 28, it was found that the treatment effect of redciclovir crossed the success stop boundary at

days

10 and 14, indicating that redciclovir outperformed placebo in treating COVID-19 patients. This finding led to a reanalysis of the chinese data.

Specifically, the report indicates that the risk ratio of the treatment with resiciclovir is independent of the difference in time required for clinical improvement (TTCI) is 1.23[ trust interval of 95%: 0.87-1.75]. In the 28-day trial, the TTCI median of the reed-seivir group was 21 days, while the control group was 23 days. The primary endpoint was defined for the study as a two-point reduction in patient admission in a 6-point scale, or a live, pre-emergent person who was discharged. The 6-point scale is 6= death; 5= hospitalization, requiring extracorporeal membrane oxygenation (ECMO) and/or Invasive Mechanical Ventilation (IMV); 4= hospitalization, need for non-invasive ventilation (NIV) and/or high flow oxygen therapy (HFNC); 3= hospitalization, requiring supplemental oxygen (but no NIV/HFNC); 2= hospitalization, but without oxygen supplementation; 1= discharge or discharge criteria (discharge criteria are defined as clinical recovery, i.e. fever, respiratory rate, return of blood oxygen saturation, and cough, all maintained for at least 72 hours); please refer to table 4. Grade =3 indicates moderate severity, and grades =4 and 5 indicate severity levels.

TABLE 4 Scale Chart

ECMO: oxygenating an extracorporeal membrane; NIV: non-invasive ventilation; IMV: invasive mechanical ventilation; HFNC: high flow nasal catheter

In contrast, preliminary results from the adaptive COVID-19 therapy trial (ACTT) [34, 35] indicate that reiciclovir results in a 31% faster rate of recovery compared to standard-of-care therapy. In particular, patients receiving Reidesciclovir treatment had a median time to recovery of 11 days, while patients receiving placebo were 15 days (p < 0.001) [34]. Due to the highly significant differences, the trial was terminated early and renamed "ACTT-1" and reidcevir became the "standard of care" for the remaining trials as part of the adaptive design [36, 37]. In contrast to the Chinese test, the preliminary results of the data in this period indicate that ACTT-1 may have "assay power too high".

To mitigate the differences between what appears to be "underassay" studies on the one hand and what might be "overdone" studies on the other hand, the present invention first considers the differences and similarities between the two assays for the primary and secondary endpoints. The invention then forms a binary endpoint for a properly defined "response" according to the definition of "rehab" used in ACTT-this idea was first proposed in [30] and listed as one of three endpoints in the most recent industry guide for COVID-19, issued by the US FDA [37 ]. The present invention then reanalyzes the data from the chinese redexivir test by performing landmark rogues regression analysis using the newly defined binary endpoint. The results from this reanalysis work should provide some insight into the efficacy of ridciclovir in chinese trials-whether this is actually an assay-deficient study, to what extent the therapeutic efficacy of ridciclovir is and in which patient groups it is effective.

Method

Ordinal scale and end point of COVID-19 severity

Both Chinese and US trials use an ordinal scale classification to indicate the severity of disease in patients on a particular day, based on the blue-map of the World Health Organization (WHO) for treatment of COVID-19 [38]. The chinese trial used a 6 point scale. The NIAID's ACTT was modified using a 7-point scale to an 8-point scale (date of revision: 3/20/2020) [33]. In addition to the reverse scale ordering, ACTT also subdivides the "live discharge" in chinese test scale into two additional categories. Furthermore, the 8-point scale in the second version of the ACTT subdivides the 5 th category in the first version into 5 th and 6 th categories. It can be noted that category 5 of the first version of ACTT corresponds exactly to category 2 of the chinese test scale. These all represent a "mildly severe" condition, i.e. the patient needs to be hospitalized but does not require supplemental oxygen.

ACTT has undergone multiple end point revisions. Before 20 days 3 months, the primary endpoint for ACTT was "percent subjects reporting each severity level on the 7-point scale"; between day 20 at month 3 and day 20 at month 4, the primary endpoint was changed to "in 8-point scale, report the percentage of subjects per severity level". After 4 months and 20 days, the primary endpoint was switched to "recovery time to day 29". The recovery day is defined as the first day that the subject satisfies one of the following three categories in the ordinal scale: 1) Hospitalization, no oxygen supplementation-no longer continuous medical care (point 6); 2) No hospitalization, limited mobility and/or the need for home oxygen (point 7); 3) There was no hospitalization and no restricted activity (point 8). During the pandemic period it is difficult to determine exactly what an appropriate endpoint should be specified, and these revisions appear to have been understood and accepted by regulatory bodies [36].

In contrast, the test in china defines the primary endpoint TTCI as "the time required to reduce the patient's admission status by two points in the 6-point scale, or live the first-onset of discharge". The percentage of subjects reporting each severity level of the 6-point rank scale is a critical secondary endpoint. IDMC uses this key secondary endpoint to monitor chinese trials [30]. The other endpoint, which is the time required to reduce 1 point, was also included in the NIAID trial as a secondary endpoint.

The end point, the time required for recovery or clinical improvement, whether defined as TTCI in the chinese trial as a 1-or 2-point improvement or the NIAID's ACTT, appears to be free of difficulties in interpreting "risk ratios" and enjoys a "median day required for response" that is more readily understood by clinicians and journalists. However, there are some technical limitations to the end of the time required for such a reaction. First, the score may fluctuate, especially when the scale is refined to more classes. Therefore, the "time required for reaction" actually means the time of the first reaction, ignoring the possibility of continuous deterioration in the following day. Secondly, the time required for improvement was of no clinical significance for patients who died during the study. For severe COVID-19 cases, the 28-day mortality rate in the Chinese trial was about 13-14% and the NIAID trial was 8-12%. For the deceased, TTCI or time to recovery was unlimited or undefined, but had been deleted on day 28 or 29. For live patients who have not yet reached the criteria of recovery or improvement at the end of the study, deletion is clearly unfair. The present invention explores the following alternative analysis methods.

Surrogate data analysis for Chinese trials

Based on NIAID's trials, where the "recovery" criteria are defined by reaching

points

6, 7 or 8, the present invention seeks the corresponding classification in Chinese trials and similarly determines the "recovery" criteria as the clinical

state reaching point

2 or 1 in a scale of 6 categories (in reverse). As expressed by clinical experts [33,34], the need to supplement oxygen to avoid critically ill patients in a pandemic crisis is of clinical interest to patients and healthcare providers.

The present invention classifies each result in the chinese test as "reacted" or "non-reacted" on each evaluation day by examining the status in the 6-point scale: the 2 nd or 1 st point is reaction; otherwise, no reaction is obtained. The present invention then analyzes the binary reaction data using the method of rogowski regression. Our analysis is based on summary data in the last IDMC meeting at 29/3/2020, shown in [30], which is close to the final test data lock reported in [29], completed at 1/4/2020. The rogues regression model includes baseline disease status, treatment groups, day of assessment, daily treatment interactions, and interactions with treatment at baseline status. Note that the model will achieve treatment efficacy adjusted with baseline status and evaluation day in the study. Our primary objective was to assess the effect of treatment on day 28 while controlling baseline status. The present invention also tested the treatment effect at day 14 to see if there was an early treatment effect 4 days after 10 days of intravenous reed-seivir therapy. Considering that there is a correlation between two analyses at two different dates, the present invention uses the Hochberg stepwise analysis method to control the overall first type error rate [39]: the hypothesis associated with the smaller p-value was examined at alpha =0.025, and the hypothesis associated with the larger p-value was examined at the alpha =0.05 level. The therapeutic effect of ridciclovir is expressed as the response odds ratio (using a 95% confidence interval) relative to placebo.

As a result, the

The data set included 231 patients (reed-ciclovir 153, placebo 78) and 225 patients (reed-ciclovir 149, placebo 76) collected at baseline and on day 28 on a 6-point ordinal scale. Baseline score distribution (%) is summarized in table 5: from point 1 (discharge or discharge criteria met) to point 6 (death), the ridciclovir groups were (0, 81.0, 17.6, 0.7) and the placebo groups were (0, 3.8, 83.3, 11.5, 1.3, 0). As can be seen, the majority (81-83%) of patients were point 3 patients, i.e. hospitalized, requiring supplemental oxygen (but not NIV/HFNC) -moderate severity category. Approximately 12-18% of patients were point 4 patients, i.e., hospitalized and required non-invasive ventilation (NIV) and/or high flow oxygen therapy (HFNC). Patients of category 5 are rare, i.e., patients requiring extracorporeal membrane oxygenation (ECMO) and/or Invasive Mechanical Ventilation (IMV).

Table 5 comparison of the ruidesavir group with the placebo group

* 1-death cases appearing before treatment were excluded from analysis

Figure 9 shows the proportion of responders (defined as less than or equal to point 2) in the different treatment groups on each study evaluation day without control of baseline status. In both treatment groups there was a clear trend of increasing response. Table 6 shows the main results of the rogue regression analysis. On day 28, the response rate was 85% for patients treated with reed-ciclovir with baseline status at point 3 (moderate severity category), and 70% for placebo-treated patients of the same category (OR =2.38, p = 0.0012). On day 14, the patients had a response rate of 43% for reed-ciclovir versus 33% for placebo (OR =1.53, p = 0.0022). After multiple test adjustments, both have significant differences. For patients with baseline status at point 4 (severe category), since the cohort was very small in the study, there were no similar comparisons with significant differences, although the response rate was numerically higher in the placebo group.

TABLE 6 results of the Rogis regression analysis

* The rogue regression model included treatment groups, baseline scale, assessment day, interaction with daily treatment, and interaction with baseline treatment.

Clearly, the rogies regression analysis at the binary end-point provided higher detectability for the data and showed that the 10-day treatment with resiscivir effectively responded to moderately severe COVID-19 patients with a 2.4-fold improvement at day 28 after the start of treatment and a 1.5-fold improvement at day 14 with a highly significant difference. Thus, although the chinese study ended up early in patient enrollment, it is not truly "underassay". However, why and how statistically valid and clinically reasonable is this rogue regression analysis? In view of these problems, the present invention provides the following:

prior to final data analysis, IDMC suggested the use of a binary endpoint combining scales =2 and 1 as "responsive" to replace the endpoint of Time To Clinical Improvement (TTCI) [29], and obtained FDA recommendations [36]. This binary response is reasonable, although it was not selected as the pre-specified primary endpoint, since COVID-19 is essentially unknown (e.g., ACTT has adapted the endpoint and sample number multiple times during the course of the experiment as the study title is properly prepared). Similar to the oncology phase II trial, in ORR (objective remission rate) analysis, complete Remission (CR) and Partial Remission (PR) are typically combined as "remission", and the remaining disease Stable (SD) and Disease Progression (DP) are combined as "no remission". The multi-scale dichotomy aggregates more events on both the "reacted" and "non-reacted" sides, thus making the comparison more distinct and enhancing the signal strength. This process makes the assay more robust than using the original multi-layer scale. Landmark analysis on day 28 (i.e. end of follow-up day) is also well understood. In contrast, the time required for rehabilitation or TTCI has an inherent problem in that the time metric of the deceased is infinite or undefined. For clinicians, binary endpoints are also of significance; after all, the decisions they make are always binary: whether the patient can be treated with such a drug. The binary endpoint is also clinically significant because patients and medical facilities can shed the burden of disease when they no longer need to be supplemented with oxygen (scale = 2) or discharged (scale = 1).

In summary, our reanalysis showed that, for moderately severe patients, reidecivir achieved good response rates with strong significant differences; despite premature termination and insufficient number of samples, a valid conclusion can be reached. Reanalysis supported the preliminary finding that ACTT was effective against reidcevir, but the present invention demonstrated that this efficacy was only applicable to patients who were not seriously covd-19 at registration, which were among the majority of hospitalized covd-19 patients. The present invention also demonstrates that, given the urgent need, reidsivir should be offered as a decision as part of the hospital standard care treatment and agrees that FDA issuance of EUA is an important step towards developing more effective therapies that can target all COVID-19 patient ranges.

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Claims

1. A graphical user interface based system for monitoring and directing an on-the-fly clinical trial on a tunable and real-time basis, comprising:

b. a boundary determination module for determining a boundary of a set of regions including a good region, an optimistic region and a bad region, wherein the boundary is adjustable as the in-flight clinical trial progresses, wherein each region represents a different risk level associated with cumulative effects of the in-flight clinical trial; and

c. a Graphical User Interface (GUI) operable with the boundary determination module for displaying a graph of the cumulative effect of the on-the-fly clinical trial and displaying boundary parameters corresponding to the set of regions, wherein the GUI allows a user to adjust values of boundary parameters based on the graph, thereby generating new boundaries in real-time as the on-the-fly clinical trial progresses, wherein the cumulative effect of the on-the-fly clinical trial is continuously projected onto the graph, thereby monitoring and guiding the on-the-fly clinical trial on an adjustable and real-time basis.

2. The system of claim 1, wherein the set of subject data comprises blinding data or one or more cumulative effects derived from the blinding data.

3. The system of claim 1, wherein the bad area comprises a null area and the good area comprises a success area.

4. The system of claim 3, wherein the GUI provides a recommendation that:

b. "terminate early due to invalidation" if the cumulative effect falls within the invalidation region;

c. if the cumulative effect falls in the good region but not the success region, "continue without modification";

5. The system of claim 1, wherein the cumulative effect is oneOne or more statistical scores selected from the group consisting of: score statistic (B value), wald statistic (Z value), and point estimation

6. The system of claim 1, wherein the boundary parameter has an ideal value specific to a phase or time.

7. The system of claim 1, operating in conjunction with a simulation module that simulates in view of accumulated trends of the set of subject data and the graph thereof, predicts future trends and trajectories of the on-the-fly clinical trial, and optionally by comparison with an initial or existing clinical trial design and assumptions for the initial or existing clinical trial design, to suggest clinical trial parameter adjustments.

8. The system of claim 7, wherein the simulation is performed by trend analysis.

9. The system of claim 8, wherein the trend analysis is a piecewise linear analysis in which different weights are assigned to each segment that exhibits a linear trend.

10. The system as claimed in claim 1, wherein the good region corresponds to a value of B not less than B ₁ (t, 1-. Beta.) region; optimistic region corresponds to B value less than B ₁ (t, 1-. Beta.) but not less than b ₂ (t,R _max ) The area of (a); and the defective region corresponding to the B value being less than B ₂ (t,R _max ) The area of (a); wherein said R _max Is the maximum sample number ratio of the on-the-fly clinical trial at time t.

11. The system of claim 3, wherein the invalid region corresponds to a B value no greater than B _f (t) region of (t) wherein b _f (t) is shown at time tA threshold value of invalid conclusion of significant difference, and the success region corresponds to a region where the B value is not less than Cs, where Cs is the threshold value representing successful conclusion of significant difference.

12. The system of claim 1, wherein the set of regions in the graph are marked with different colors or patterns.

13. The system of claim 1, wherein when the running clinical trial continuously falls within the optimistic region for 10 points, the system provides a signal indicating a need to adjust one or more clinical trial parameters of the running clinical trial.

14. A graphical user interface based method for monitoring and guiding a clinical trial in progress on a tunable and real-time basis, comprising:

c. performing the boundary adjustment on a Graphical User Interface (GUI), wherein the GUI displays a graph of the cumulative effect of the on-the-fly clinical trial and boundary parameters corresponding to the set of regions, the GUI allowing a user to adjust the values of the boundary parameters based on the graph, thereby generating new boundaries in real-time as the on-the-fly clinical trial progresses,

wherein the cumulative effect of the on-the-fly clinical trial is projected continuously onto the graph; and

d. providing, via the GUI, a recommendation that directs the on-the-fly clinical trial, wherein the recommendation is to:

15. A graphical user interface based method for diagnosing a completed clinical trial, comprising:

b. mapping, by a boundary determination module, boundaries of a set of regions including a good region, an optimistic region and a bad region, the boundaries being adjustable in applying the information, wherein each region represents a different risk level associated with cumulative effects of the clinical trial;

d. providing, via the GUI, a diagnosis of the clinical trial assuming the clinical trial is in operation, wherein the diagnosis is: